CHAPTER III

THE ANTISCORBUTIC VITAMINE[22]

[22] Vitamine is used throughout this monograph as synonymous with "accessory food factor" or "food hormone" as a convenient descriptive term, without any intention of connoting a definite chemical substance.

We shall not discuss the subject of vitamines in general, but confine ourselves to the more limited field of the antiscorbutic vitamine. The recognition of the "accessory" dietary factors is of such recent date, however, that it will be well to consider briefly how attention came to be directed to them and how their existence was ascertained. As in the case of so many scientific discoveries, it is difficult to point to the exact time when the advance was made. On looking back we find that Lunin, in 1881, noting that mice were unable to live on a diet consisting of protein, fats, carbohydrates, salts and water, came to the conclusion "that other substances indispensable to nutrition must be present in milk besides caseinogen, fat, lactose and salts." This work did not stimulate similar investigations, nor did Lunin, as might have been expected, allude to scurvy. The work which focussed attention on this novel aspect of dietetics was the report of Eijkman, in 1897, to the effect that when fowl are fed decorticated rice, they develop a disease resembling beriberi, and that the paralytic symptoms disappear on feeding them rice polishings or its alcoholic extract. Here, for the first time, was a positive rather than a negative experiment, and one capable of simple verification. The subject was placed on a scientific basis by the classic investigation of Hopkins, who experimented with purified food substances, and demonstrated how diets which were deficient could be rendered adequate. As early as 1906 he wrote "the animal body is adjusted to live either upon plant tissues or other animals, and these contain countless substances other than the proteins, carbohydrates and fats." "In diseases such as rickets, and particularly in scurvy, we have had for long years knowledge of a dietetic factor, but though we know how to benefit these conditions empirically, the real errors in the diet are to this day quite obscure." The work of Osborne and Mendel, and McCollum and Davis in this country, of Schaumann, Funk, Stepp and others, all led to the conclusion that purified diets are unable to satisfy the nutritive requirements of rats or mice, and that extracts of the natural foods suffice to render the diet adequate.

The same rule holds for man, who, when deprived of these vitamines, develops the so-called deficiency diseases--typically modern disorders. Regarded as a group, they are a consequence of our altered mode of life and peculiar civilization. They follow naturally upon the development of immense cities housing millions of people, who necessarily must receive perishable foodstuffs produced at a great distance. To even a greater extent they are the product of countless ingenious methods devised mainly to render foods stable--drying, heating, the addition of preservatives--most of which accomplish their object, but incidentally rob the food of its essential vitamine.

None of the vitamines has been isolated in a pure state. The nearest approach to this desired end has been the work of Funk, who obtained the water-soluble vitamine in a state of such concentration that about 3 mg. sufficed to cure a pigeon of polyneuritis. In considering the attributes of the antiscorbutic vitamine, it must be borne in mind that this factor is referred to as it exists in various foods; for example, in orange juice or in cabbage, and furthermore, that the method of ascertaining its presence or concentration is limited to the crude biological test of animal feeding.

The antiscorbutic factor is distinguished by being the most sensitive of the three vitamines, the most unstable, the least resistant to physical or chemical processes. It may be regarded as one of the most delicate indicators of the biological integrity of foodstuffs; however, as Falk and his co-workers have shown, the enzyme property of living matter is still more readily destroyed. The antiscorbutic vitamine is soluble in water, and therefore is termed by some the "water-soluble C" factor. It is also soluble in alcohol, as shown by the experiments of Hess and Unger and of Harden and Zilva, and the therapeutic tests on infants of Freise and of Freudenberg.[23] It possesses, therefore, the solubility of the water-soluble vitamine. Some have suggested that it may be derived from this vitamine, others that instead of one there may be a series of antiscorbutic factors--suggestions based on pure hypothesis. Holst and Froelich showed that this vitamine passes, without appreciable loss, through dialyzing parchment, and Harden and Zilva (2) that it can pass through a porcelain filter. The latter, using the method of Seidell, demonstrated that this vitamine is not adsorbed by fine precipitates such as fuller's earth, differing in this respect from the water-soluble vitamine; and that in a mixture of equal volumes of autolyzed yeast and orange juice, the antiscorbutic vitamine remained unaffected, whereas the water-soluble A was entirely removed.

[23] Freise cured a case of infantile scurvy by giving about 2 c.c. of an extract obtained from turnips by means of absolute alcohol. Seven weeks were necessary to cause a disappearance of symptoms. Freudenberg employed an extract of carrots, prepared with 96 per cent. alcohol, and effected a quicker cure.

One of the most distinctive characteristics of the antiscorbutic factor is its _sensitiveness to even moderately high degrees of heat_. In this respect it differs markedly from the water-soluble or so-called "antineuritic vitamine" which withstands exposure to high temperature. The reaction of the antiscorbutic vitamine in this regard is not a simple one, and cannot be expressed by a mere statement of the degree of heat and the length of exposure. Numerous other factors, especially the reaction of the medium, but also the physical environment, must be taken into consideration--for example, cabbage is more resistant to the action of heat than its juice. An understanding of the relation of antiscorbutics to heat may perhaps best be obtained by considering the subject in connection with some definite foodstuffs. The most exhaustive study from a quantitative standpoint is that of Delf. She showed that when cabbage is subjected for an hour to a temperature of 80° to 100° C., 90 per cent. of its antiscorbutic vitamine is lost, and that 80 per cent. is lost when a temperature of 90° to 100° is maintained for twenty minutes, or a temperature of 60° for a period of sixty minutes. This experiment shows that the destructive influence of heat is enhanced to a comparatively slight degree by a rise of temperature, only about threefold when it is raised from 60° C. to the boiling point. This result points to a temperature coefficient of about 1.5 to 10° C. of temperature. It is suggested by Delf that this low coefficient of destruction is opposed to the enzyme or protein-like theory of the nature of the vitamine, and suggests a simpler constitution. On the other hand, we must bear in mind that the proteins which have been used in experiments and found to possess a high coefficient of heat, have been tested in the pure state, whereas the vitamine of the cabbage is bound up in the cell.

Experiments with this vitamine as found in milk accord with the above investigation, demonstrating that intensity of heat is not as destructive as prolonged heating. This agrees with the clinical experience that milk which has been boiled for a few minutes does not induce scurvy as readily as pasteurized milk which has been heated for 45 minutes to 140° or 165° F. (Hess and Fish).

As demonstrated by tests with orange and with lemon juice, the antiscorbutic vitamine is greatly protected from the destructive effect of heat when it is associated with an acid. This was shown first by Holst and Froelich and has been confirmed by numerous observers. An excellent example of marked thermostability conferred on a food by its acid reaction is furnished by the tomato, which is strongly antiscorbutic even after it has been subjected to the canning process. Conversely, Harden and Zilva have shown that the vitamine is destroyed by alkali even when dilute (one-fiftieth normal sodium hydrate) and kept in contact at room temperature; this alteration does not take place at once, but in the course of several hours.

It is true that the antiscorbutic factor is peculiarly sensitive to _drying_, but there are exceptions to this rule, so that it is incorrect to state, as does the British Report of the Medical Research Committee, that "it may be regarded as an axiom that dry or dried foodstuffs will not prevent scurvy." We have shown that fresh milk dried by the Just-Hatmaker process may retain by far the greater moiety of its virtue. In this regard rapidity of desiccation and subsequent protection from oxidative processes are important factors. The general rule holds true, however, that this vitamine, in contradistinction to the "water-soluble" vitamine, is readily damaged and destroyed by drying.

This vitamine is peculiarly sensitive to _aging_, especially when it is present in an alkaline or neutral medium; but even in an acid medium its potency soon diminishes. Harden and Zilva found this to be the case with lemon juice stored for a fortnight in the cold room, and our experience has been similar in regard to orange juice kept in the refrigerator under a layer of liquid petrolatum. In milk the antiscorbutic factor diminishes with age, especially following pasteurization, in the course of which most of the acid-forming bacteria have been destroyed. Aging has the least effect when the food with which the vitamine is associated has been dried. This is true not only of lemon and of orange juice as demonstrated experimentally and clinically, but even of milk, which even after it has been dried and stored for months, may still possess marked curative value.[24]

[24] Reference is made to a milk dried by the Just-Hatmaker process, containing about 3 per cent. of moisture. The clinical data on which this conclusion is based are given in the previous chapter.

Experiments by Harden and Zilva showed that exposure of lemon juice to _ultra-violet rays_ for eight hours does not influence its antiscorbutic activity, that exposure of autolyzed yeast for the same length of time likewise does not impair its "antineuritic" potency, but that under identical conditions the fat-soluble factor in butter becomes inactivated. Similar tests carried out by the author with orange juice led to the same result. It thus appears that one of the vitamines--not the most unstable--manifests a peculiar sensitiveness to a certain form of physical or chemical action.

In view of the fact that _shaking_ partly destroys pepsin and rennin, as shown by Shaklee and Meltzer, it would be of interest to ascertain whether this process brings about any impairment of the antiscorbutic vitamine. Particular interest is attached to this question because it is generally recognized that milk loses some of its potency in the course of handling--whatever may be comprised by this term. In experiments on the fat-soluble vitamine Steenbock and his co-workers found that "somewhere in the course of the manipulation to which the butter fat had been subjected, factors had been introduced which were responsible for a vitamine destruction."

Before discussing the question of the manner in which the antiscorbutic vitamine functionates, it may be well to state briefly the type of the disturbance which its deficiency occasions. The chief manifestation is damage to the integrity of the endothelium of the vessels, resulting in hemorrhage--whether from diapedesis or from rhexis or both of these conditions, the microscope does not inform us. Nor can it be stated positively that the endothelium has not been injured by a secondary toxic or bacterial factor. However this may be, the end result of the deficiency is endothelial damage, a pathologic condition which may be demonstrated clinically in scurvy by the "capillary resistance test" (chapter VII). The other marked functional alteration in scurvy is increased susceptibility to infection; but how a vitamine deficiency induces this vulnerability cannot be explained. Clinical tests show that the blood contains sufficient antitoxin (diphtheria) to afford protection. Harden and Zilva found that "guinea-pigs fed on an unrestricted mixed diet, on a quantitatively restricted mixed diet, and a scorbutic diet showed no differentiation in amboceptor and agglutinin titres, and in the complement activity of the blood." If this is to be interpreted as indicating that the protective substances of the body undergo but little alteration, we must consider whether susceptibility to infection, as well as tendency to hemorrhage, is not due largely to alteration in the cement substance of the endothelial and epithelial membranes.

=The Mode of Action of the Vitamine.=--One of the most interesting as well as puzzling questions in regard to the antiscorbutic vitamine concerns the manner in which it prevents or cures scurvy. It is a subject which at present is in a state of flux, hardly having emerged from the realm of hypothesis, so that detailed consideration will profit little. At first the _modus operandi_ was explained and accepted as enzyme action, but it was soon evident, in view of the thermostability of the vitamine, that it could not be classed as a ferment or enzyme in the generally-accepted sense of this term. In general, it may be stated that there are two main views: one that the vitamine acts directly, and the other that it acts indirectly through the function of the endocrine glands. _Direct action_, furthermore, may be accomplished in at least one of three ways. The vitamine may (1) serve as a source of nutriment for the tissues, (2) exert an antitoxic effect on toxic products, or (3) function as a catalyzer. The first interpretation is evidently the simplest and conforms to the long-established knowledge of caloric food factors. That such small amounts as 2 c.c. of orange juice daily should suffice to protect an animal from nutritional disaster runs counter, however, to former conceptions of food nutrition. Further than this there is little against this viewpoint. In its favor is the fact that, up to a certain point, antiscorbutics act in direct ratio to the amount given; for example, 2 c.c. of canned tomato juice is insufficient to prevent scurvy in guinea-pigs, 3 c.c. will protect some but not all of a series, whereas when the amount is increased to 4 c.c. daily all animals will be saved. As we are considering new food factors it is manifestly unwise to judge them by old standards, and to decide offhand that they cannot possess such a high degree of nutritive power. This question must be regarded as still open.

The antitoxic theory suffers from the fact that the toxic origin of scurvy cannot be established. Before this is possible, it is clear that it will be difficult to bring forward convincing evidence of a neutralizing substance. Against this theory is the fact that elimination therapy is of no avail in the treatment of infantile scurvy. Hess and Unger (1919) failed to alleviate the symptoms by means of catharsis, diuresis, sweating and repeated intravenous injections of normal salt solution. In its favor it may be advanced, in a general way, that the vitamine, in many characteristics, resembles an antitoxin--in its extreme lability, its destruction by heat, aging and alkalies. On the other hand, antitoxins also are readily destroyed by acid which, as has been shown, exerts a protective influence on the antiscorbutic factor. The rapidity of action of the vitamines, one of the most impressive phenomena, calls to mind the neutralizing action of an antitoxin, and probably has given rise to the analogy. Williams suggests that the vitamines have "a general, non-specific, antitoxic or eliminative action" on toxic substances resulting from the metabolic decomposition of food.

The theory has been advanced that the action of the vitamines is catalytic. Although this viewpoint has been taken regarding the water-soluble rather than the antiscorbutic vitamine, it will be well to review briefly the work on which it is based. Among the first to suggest this hypothesis were Vedder and Clark, who noted a relationship between the amount of vitamine required by fowls and their carbohydrate intake. Funk in 1913 made a similar observation in regard to beriberi, and in the following year, with von Schoenborn, showed that a vitamine-free diet led to hyperglycæmia, with diminished amount of hepatic glycogen, and that the addition of water-soluble vitamine diminished the hyperglycæmia and increased the liver glycogen. The work of Burge and his co-workers on the catalase content of tissue led to a similar conclusion. Their results may be summarized by the statement that the oxidative processes are hampered and fail to balance the autolytic changes, and, furthermore, that a relationship exists between the catalase activity, acidosis and normal oxidative processes. This theory would presuppose that scurvy is due to the formation of toxins which are normally in process of continual destruction in the body. According to some, these catalyzed toxic substances are metabolic in character, originating from incompletely oxidized food; according to another interpretation, they are the product of autolyzed tissue cells (tissue toxins). The difficulty with this explanation is that scurvy cannot be prevented or cured by a diet containing food of high catalytic power. For example, wheat embryos which, according to recent investigations of Crocker and Harrington, have a high catalytic activity, were found of no therapeutic value in relation to infantile scurvy (Hess, 3).

This problem has been approached from quite a different angle. As is well known, certain bacteria require serum, blood, milk, etc., in order to grow satisfactorily on artificial culture media. It has been established recently, primarily by the work of Lloyd, that this peculiarity in the cultivation of microörganisms is due largely to their requirement of vitamine. She found a relationship of the inverse order between the amount of amino acid present in the culture medium and the amount of vitamine required to stimulate the growth of strains of meningococcus. Reasoning from this experience, she suggests that the action of the accessory growth factors is to increase the reaction velocity of the proteolytic metabolism. Here we find the vitamines once more regarded as catalyzers. This author, however, associates their activity with proteolytic rather than with carbohydrate metabolism. Interesting and suggestive work of similar nature has been carried out in relation to the growth of protozoa and of yeasts (Eddy). Investigations of this kind, dealing with unicellular organisms propagated on a simple food, have the advantage of greatly simplifying the problem.

The recent work of Dutcher falls under this caption, differing merely in the fact that he attributes to the vitamines an _indirect action_. He has demonstrated that the tissues of polyneuritic birds show a decrease in catalase activity to a point 56 per cent. below normal, and that this activity is largely restored when the birds are cured with vitamine. According to this writer the vitamine functions as a metabolic stimulant, and its lack results in a depression of the body oxidations with an accompanying formation of toxic metabolic products, injurious to the nervous system. The action is regarded as coming about in an indirect manner, being accomplished through the hormone action of the vitamines on one or more glands of internal secretion.

The _endocrine hypothesis_, suggested by Funk in his monograph, is not without some corroborative evidence. In testing the pharmacologic action of the water-soluble vitamine, Uhlmann found that it stimulated the various glands of the digestive tract, in this respect acting like pilocarpine. Some years ago Albert expressed the opinion that the action of this vitamine was "vagotropic" like atropine, and recently Dutcher has reported definite relief and cessation of polyneuritic symptoms by means of pilocarpine (0.5 mg. subcutaneously). He claims equally good results from thyroxin, the hormone of the thyroid gland, from desiccated thyroid and from tethelin (pituitary). Voegtlin and Myers conclude, as the result of experiments with brewers' yeast, that the chemical and physical properties of secretin and vitamine are identical.

The early work of Funk and Douglas, which showed that various _glands of internal secretion_ diminish in size and undergo degenerative changes when the diet is vitamine-free, the newer work of McCarrison and of Dutcher to the same effect, clearly point to an intimate relationship between some of the endocrine glands and the vitamines. As regards scurvy, the only work is that of Rondoni, McCarrison and of LaMer and Campbell on the adrenal glands, which were found by all to be enlarged in guinea-pigs suffering from this disorder. These investigations must be regarded as tentative rather than conclusive until confirmed by similar necropsy reports in man. In this connection it should be noted that thyroid, parathyroid or suprarenal extract is of no avail in the treatment of scurvy. This failure may, however, be explained by the fact that the normal balance of glandular activity was not established. We must bear in mind, however, that although the vitamines may influence the secretion of the glands of internal secretion, this explanation does not satisfactorily account for the symptoms of the "deficiency diseases." These disorders do not in the slightest respect resemble the clinical pictures which we are accustomed to associate with a lack of activity of the glands of internal secretion. If the polyneuritis of beriberi and the hemorrhages of scurvy are attributable to a diminished secretion of the endocrine glands, then it will be necessary to revise present conceptions of their physiologic functions.

=The Fate of the Vitamine in the Body.=--One of the most important questions in relation to the antiscorbutic vitamine, quite apart from its chemical nature, physiologic function, and its source, is its fate in the human body after it has reached the alimentary canal or been carried to the tissues. It can be readily appreciated that our knowledge of this aspect is very meagre. We shall endeavor, however, to detail what little is known of this subject, conscious of the fact that investigations of the next few years may contradict our present viewpoints.

Most of the constituents necessary for the construction of tissue or for carrying on its functions can be synthesized by the animal body from the basal foodstuffs. It has been ascertained within the past decade that certain constituents--for example, some amino-acids of the protein molecule--are building-stones which cannot be primarily elaborated by the cells, but must be supplied by the food. At present the vitamines--including the antiscorbutic vitamine--are included in this new and essential group of substances which the human organism cannot manufacture. Animal experiments seem to bear out this conception of the vitamine whether we regard them as dynamic or as indispensable tissue elements in the structural sense.

A closely-related but less fundamental question is that of _the ability of man to store vitamines_--whether the tissues can hoard an excess of these factors, or whether, in this respect, we are carrying on a precarious hand-to-mouth existence in regard to cellular nutrition. It is of course clear that at all times the various organs and tissues must contain a certain amount of the vitamines. This has been shown for the water-soluble or "antineuritic vitamine" by the fact that even the organs of birds which have died of polyneuritis contain an appreciable quantity of the specific vitamine, although an insufficiency of this very factor has led to their death. That such is the case is demonstrated for the antiscorbutic vitamine by the fact that muscle tissue contains sufficient antiscorbutic to protect individuals subsisting largely on a diet of which raw meat constitutes the sole antiscorbutic agent (Stefánsson). It is very probable that some organs contain more of the vitamines than others; this has been proved for the "antineuritic" factor, and seems to hold good for the antiscorbutic--the liver being particularly rich. No quantitative study has been carried out from this point of view regarding the antiscorbutic vitamine, and it would be well worth our while to ascertain the relative antiscorbutic potency of the various organs of the body. Some time ago we undertook experiments to determine whether the guinea-pig is capable of storing this vitamine. One series of guinea-pigs was fed daily 6 c.c. of orange juice for a period of two weeks, whereas another series, of about the same weight, was given, in addition to the basal ration, only 3 c.c. per capita (the minimal protective dose). After this preliminary period both series were placed on a diet containing practically no antiscorbutic. Both groups came down with scurvy after about the same interval, leading to the conclusion that there could have been little if any storing of the excess vitamine by those which received twice the "minimal protective dose." The experiments of Harden and Zilva, who fed a concentrated lemon juice, showed that this potent agent also was unable to provide against a subsequent period of antiscorbutic deficiency. It should be realized that the results of these tests on guinea-pigs cannot be applied to man without tests on other species.

It might be thought that _the blood_--the purveyor of the vitamines to the tissues--would be particularly rich in these essential factors. Such, however, was not our experience in respect to the antiscorbutic vitamine. The blood possibly varies greatly in this respect according to the diet of the individual, or even according to the interval elapsing after the ingestion of antiscorbutic food. Our opinion is based on the surprisingly poor therapeutic effect of blood transfusion in the treatment of scurvy. To illustrate: An infant weighing about fifteen pounds received six intravenous injections of citrated blood--one of 200 c.c., given by the direct method, and a month later five smaller transfusions with citrated blood, which aggregated 205 c.c.[25] In spite of this addition of blood, the hemorrhage and congestion of the gums did not disappear, nor the general condition improve, as would have happened had 50 or 75 c.c. of orange juice been given by mouth. It seems probable that small quantities of vitamine are being transmitted at all times by the blood and supplied to the cells, but that its normal content of this factor is not great. The antiscorbutic potency of blood may perhaps be compared to that of milk. Animal investigation may show that various vessels--for example, those supplying or draining certain glandular organs--differ in the antiscorbutic quality of the blood which they carry. It is evident, therefore, that many transitory factors may influence the vitamine content of the blood, and that--as in the case of milk and fruits and vegetables--we are not dealing with a constant and unvarying agent.

[25] The dates and quantities of the transfusions were as follows: March 26th, 200 c.c.; April 27th, 30 c.c.; April 28th, 35 c.c.; April 29th, 30 c.c.; May 2nd, 75 c.c.; May 3rd, 35 c.c.

Nothing whatsoever is known concerning the _excretion_ of the antiscorbutic vitamine. No attempts have been made to recover it from the urine, or to ascertain if, when large amounts are ingested, the excess is thrown off by the body. This suggests the question--a corollary of that raised in connection with the vitamine content of the blood--whether it is immaterial if the vitamine is taken frequently in small amounts, or is provided only occasionally and at longer intervals in larger amounts. Is it of no moment whether the infant receive its quota of antiscorbutic every few hours through the medium of the breast milk, or only once a day in the form of orange juice or tomato? If we turn to studies on the other vitamines for enlightenment as to the possibility of excretion, we find that Muckenfuss recovered the water-soluble factor from ox bile and from human urine.[26] In this article he proposes the interesting question of a possible variation in the vitamine output under pathological conditions, which may be responsible for the development of functional disturbances in children.

[26] This investigation was carried out by means of activating fuller's earth with these fluids. This method is inapplicable to the antiscorbutic vitamine, which is not adsorbed by this material. An attempt to feed concentrated human urine to guinea-pigs resulted in their death.

It would be of interest to know the _fate of the antiscorbutic vitamine in the gastro-intestinal tract_. How is it affected by a lack of the acid gastric juice, or by the alkaline intestinal secretions, or by the bacteria in the lumen of the gut? From which part of the intestine is it largely absorbed? May an appreciable amount undergo destruction before this is accomplished? None of these questions can be answered satisfactorily in the present state of our knowledge, but they suggest that the mere fact that an adequate quota of antiscorbutic vitamine is provided in the food does not necessarily insure an adequate supply for the tissues. If in addition to the question of intake we must take into account that the vitamines may suffer various vicissitudes, it may come to pass that pathological conditions at times destroy or render them partially inactive. In this way we may account for irregularities in the clinical course of disorders associated with vitamine deficiency.

Of prime importance, however, is the effect of the vitamines _on the glands of the alimentary tract and on the digestive processes_. A diminution of gastric juice, or in some instances a total absence, has been observed in adult scurvy, and noted by us in two cases of infantile scurvy. As mentioned elsewhere, some consider the function of the water-soluble vitamine analogous to that of secretin. In applying this hypothesis to scurvy it must be borne in mind that the sequence may be reversed, that the lack of vitamine may not lead to the gastric achylia, but that the achylia may come about secondarily as the result of the malnutrition.

We have referred to _"irregularities" in the course of the "deficiency diseases."_ A careful perusal of the literature leaves one with the impression that the most experienced observers are not entirely satisfied with the exclusively etiologic relationship of the vitamine to its respective nutritional disorder. In regard to scurvy, more particularly, there are numerous scattered reports where the disorder did not yield to antiscorbutic foods as might have been expected, or where, on the other hand, it suddenly and inexplicably retrogressed, although there had been no alteration in the dietary.[27] These instances are not common, but they occur from time to time, and their occurrence must be accounted for. In relation to beriberi and avian polyneuritis improvement of this kind has frequently been explained on the theory of a sudden mobilization of vitamines from the tissues. There is, however, no data on which to base such explanations, and it may be that a lack of parallelism between vitamine intake and the clinical course may be due at times to processes taking place in the alimentary tract.

[27] Neumann, for example, writes that he has seen at least four children whose condition was not improved, although in addition to the milk, they took asparagus, spinach, and other vegetables or apple sauce. Some years ago we had a similar experience. It has likewise happened that infantile scurvy did not recur, although the diet was the same as that which originally led to the disorder.

The fat-soluble vitamine has been termed by some the growth vitamine. All the vitamines, however, are closely associated with the function of growth, which their deficiency tends to inhibit. In the chapter on symptomatology, it will be pointed out that infants suffering from scurvy fail to grow normally both in length and in weight. To a certain extent this may be due to a loss of appetite, which is one of the characteristic phenomena accompanying the scorbutic condition. On the other hand, this anorexia may be secondary and not primary to the impairment of the growth impulse, which may lead to a dysfunction of various body processes.

It is of little value to look ahead and try to foresee what the next decade will bring forth in regard to the nature of the vitamines. Investigation has broadened remarkably during the past few years and now embraces the chemical field--chemical and adsorption methods, the large realm of biology, including studies in physiology and pharmacology; and recently pathology has once more been called upon to aid in the solution of the problem. Probably additional vitamines will be discovered. From time to time it has been suggested that a specific growth vitamine exists quite distinct from the three which are recognized, and recently Mellanby has suggested still another food factor--a specific "rachitic vitamine." When we reflect that the characteristic functions of the various organs--the kidneys, liver, etc.--must depend on essential differences in chemical structure, the complexity of the entire problem of unidentified factors becomes evident.[28]

[28] For recent and comprehensive reviews of the vitamines the reader is referred to papers by A. B. Macallum (Trans. Royal Canadian Institute, Toronto, 1919) and by W. H. Eddy (Abstracts of Bacteriol. 1919, Vol. iii, 313.)